CN104829675B - A kind of compound and crystal formation and preparation method thereof and purposes - Google Patents
A kind of compound and crystal formation and preparation method thereof and purposes Download PDFInfo
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- CN104829675B CN104829675B CN201510232749.3A CN201510232749A CN104829675B CN 104829675 B CN104829675 B CN 104829675B CN 201510232749 A CN201510232749 A CN 201510232749A CN 104829675 B CN104829675 B CN 104829675B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention discloses compound shown in formula I, R1、R2、R3It is respectively selected from methyl, ethyl, propyl group, butyl, amyl group or hexyl.The invention also discloses the crystal formation of a kind of compound, and their preparation method and purposes.The compound of present invention offer or its crystal formation, inhibited to Leukemia Cell Lines MV4 11 cell proliferation, provide a kind of new selection for screening treatment or prevention leukemia medicament clinically.
Description
Technical field
The present invention relates to a kind of compound and crystal formation and preparation method thereof and purposes.
Background technology
Herba Leonuri begins to be loaded in Shennong's Herbal, original name motherwort, is listed in top grade.Compendium of Material Medica is referred to as
" panacea of blood man ", cures mainly " vaginal bleeding during pregnancy is had difficult labour, placenta retention, bruise, blood wind, blood pain, metrorrhagia and metrostaxis, hematuria ", for gynecological's multiparity
Key medicine.
Herba Leonuri mainly contains alkaloid, terpenoid, flavone, iridoid glycoside, phenethyl alcohol glycoside, volatile oil, peptide
The composition such as class and fatty acid, mainly alkaloid and the Diterpenes that its activity research is more:
(1) alkaloid: mainly include stachydrine, leonurine, Herba Leonuri pyridine and leonurinine etc.；
(2) diterpene: increase its study of active components in recent years, wherein Leoheteronin A and Leopersin G is bright
Aobvious acetylcholine esterase inhibition activity, has good prospect in terms for the treatment of Alzheimer；Prehispanolone is one
Plant the platelet antagonism factor, platelet aggregation can be suppressed；Leojaponin has guarantor to the cerebral cortex cells of injured with glucose deprivation
Protect effect；The labdane type diterpenoids that Khan obtains has antiinflammatory action etc..
In prior art, from Herba Leonuri, extract the compound obtained be mainly terpenoid, alkaloid etc., such as: in
State's patent CN 103211809 A discloses to extract from Herba Leonuri and has obtained formula A compound, has anticoagulant effect；China
Patent CN 103553919 A discloses to extract from Herba Leonuri and has obtained formula B compound, has certain increasing to coagulation function
Pretend use；Chinese patent CN 104086559 A discloses to extract from Herba Leonuri and has obtained formula C compound, has antiplatelet
The effect assembled.
At present, there are no the relevant report of the compounds of this invention and crystal formation thereof, more there are no its preparation method and purposes
Relevant report.
Summary of the invention
It is an object of the invention to provide a kind of compound and crystal formation, this compound and crystal formation to Leukemia Cell Lines MV4-
11 cell proliferation are inhibited.
Compound shown in the formula I that the present invention provides:
Wherein, R1、R2、R3It is respectively selected from methyl, ethyl, propyl group, butyl, amyl group or hexyl.
Further, described compound is as shown in formula II:
Present invention also offers the preparation method of compound shown in formula II, it comprises the following steps:
A, take Herba Leonuri medical material, after adding ethanol extraction, remove solvent, obtain ethanol extract；
B, by ethanol extract with water-dispersible, successively with ethyl acetate, n-butanol extraction, combined ethyl acetate part, remove
Solvent, obtains ethyl acetate extract；
C, take ethyl acetate extract, use silica gel column chromatography, successively with petroleum ether: acetone=100:1,50:1,25:1,
10:1,5:1 are that eluant carries out gradient elution, take petroleum ether: eluent during acetone=5:1, according to thin layer tracking, merging contains
There are the eluent of similar compositions, recycling design, obtain component G；
D, take component G, use anti-phase polystyrene type resin column chromatography, successively with methanol: water=50:50,75:25,85:
15,95:5 is that eluant carries out gradient elution, collection methanol: eluent during water=85:15 and/or 95:5, chases after according to thin layer
Track, merges the eluent containing similar compositions, recycling design, obtains component G7；
E, take component G7, use alkaline silica gel column chromatography, successively with petroleum ether: acetone=15:1,10:1,8:1 is as eluting
Agent carries out gradient elution, collects petroleum ether: eluent during acetone=8:1, according to thin layer tracking, merging is containing similar compositions
Eluent, recycling design, obtain component G7-4；
F, take component G7-4, peroxidating aluminum column chromatography, with petroleum ether: ethyl acetate=20:1 is that eluant carries out eluting,
Follow the trail of according to thin layer, collect the eluent containing target compound；
G, take the eluent containing target compound, recycling design, through preparing thin layer, obtain target components, then use
Reverse phase liquid preparative hplc, with 93%v/v methanol aqueous solution eluting, collects target compound, recycling design, to obtain final product.
Further,
In step a, Herba Leonuri medical material is 1:8～24kg/L with the w/v of ethanol, and described ethanol is 95%v/v second
Alcohol；
In step b, ethanol extract is 1.2:8kg/L with the w/v of water, water, ethyl acetate, the volume of n-butyl alcohol
Ratio is 1:1～6:1～6；
In step c, the condition of gradient elution is as follows:
In step d, the condition of gradient elution is as follows:
In step e, the condition of gradient elution is as follows:
In step f, component G7-4 is 1:600g/mL with the w/v of eluant.
Further,
In step d, polystyrene type resin is MCI gel CHP 20P；
In step g, the developing solvent preparing thin layer is petroleum ether: acetone=5:1.
The crystal formation of compound shown in the formula II that the present invention provides, this crystal formation is monoclinic system, and space group is P21, structure cell is joined
Number is, α=90.00 °,, β=97.2458 (13) °,, γ=90.00 °, Z=4, unit cell volume is 。
Present invention also offers the preparation method of above-mentioned crystal formation, it comprises the following steps:
1., according to above-mentioned method, compound shown in formula II is obtained；
2., compound shown in modus ponens II, add methanol, be placed on equipped with in the exsiccator of desiccant, place to separating out
Crystal, obtains the crystal formation of compound shown in formula II.
Further, step 2. in, the w/v of compound shown in formula II and methanol is 1:0.01～0.1mg/ml.
Further, described desiccant is selected from variable color silica gel.
Above-claimed cpd or its crystal formation purposes in preparation treatment or prevention leukemia medicament.
A kind of pharmaceutical composition that the present invention provides, it be with above-claimed cpd or its crystal formation, pharmaceutically acceptable salt,
Hydrate or solvate are active component, add the preparation that pharmaceutically conventional adjuvant or complementary composition prepare.
Further, described preparation is through gastrointestinal absorption preparation or ejection preparation.
The compound of present invention offer or its crystal formation, inhibited to Leukemia Cell Lines MV4-11 cell proliferation,
A kind of new selection is provided for screening treatment or prevention leukemia medicament clinically.
The present invention can use preparation technique means or the pharmaceutical methods of this area routine, is prepared as by the crystal formation of the present invention
Suitable medicine type, comprises: tablet, injection, tincture, suppository, capsule, unguentum (ointment, ointment), ophthalmically acceptable system
Agent, pill, implant, syrup, mist agent (aerosol, powder spray, spray), membrane, granule, oral solution is (oral
Suspensoid, Orally taken emulsion), powder, aural preparations, nasal formulations, lotion (irrigation, enema), liniment (varnish, film
Agent), gel, patch etc.；It is preferably tablet, capsule, ophthalmic preparation.Wherein, described tablet is selected from buccal tablet, Sublingual tablet, mouth
Chamber paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet, enteric coatel tablets etc.；Described injection selected from injection,
Transfusion, freeze-dried powder, emulsion, implant, microball preparation, pellet preparations etc.；Described capsule is selected from hard capsule, soft capsule, delays
Release capsule, controlled release capsule and enteric coated capsule etc.；Described ophthalmic preparation is selected from eye drop, collyrium, intraocular injection solution, eye ointment
Agent, ophthalmically acceptable ointment, gel for eye, eye mask agent, eye pill, ophthalmic intercalating agent etc.；Described pill is selected from drop pill, sugar pill etc.；
Described granule is selected from mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules, controlled release granule etc.；Described aural preparations is selected from
Ear drop, ear lotion, ear spray, ear ointment, ear ointment, ear gel, earplug, ear powder, ear are used
Pill etc.；Described nasal formulations is used dissipate selected from nasal drop, nasal douche, nasal spray, nose ointment, gel for nose, nose
Agent, powder nose inhalant, nose stick etc..
Obviously, according to the foregoing of the present invention, according to ordinary technical knowledge and the customary means of this area, without departing from
Under the present invention above-mentioned basic fundamental thought premise, it is also possible to make the amendment of other various ways, replace or change.
The detailed description of the invention of form by the following examples, remakes the most specifically the foregoing of the present invention
Bright.But this should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to Examples below.All based on foregoing of the present invention
The technology realized belongs to the scope of the present invention.
Accompanying drawing explanation
Fig. 1 is the single crystal diffraction structure chart of formula II compound crystal form.
Detailed description of the invention
The raw material, the equipment that use in the specific embodiment of the invention are known product, obtain by buying commercially available prod.
Embodiment 1
(1) experiment material:
1. medical material
Herba Leonuri picks up from Wenjiang District, Chengdu, Sichuan, is accredited as through TCD identification teaching and research room of Chengdu University of Traditional Chinese Medicine professor Li Min
The herb of labiate Herba Leonuri Leonurus japonicus Houtt..
2. reagent and filler
Column chromatography silica gel, 200～300 mesh (SILVER REAGENT), it is purchased from Qingdao Haiyang silica-gel desiccant factory；
Alkaline silica gel, 300-400 mesh (SILVER REAGENT), it is purchased from Shanghai Sheng Ya Chemical Co., Ltd.；
Tlc silica gel G, GF254With H (chemical pure), it is purchased from Qingdao Haiyang silica-gel desiccant factory；
Chromatography (neutral) aluminium oxide, 100 mesh～200 mesh (chemical pure), it is purchased from land, Shanghai all chemical reagent factories.
MCI gel CHP 20P, 75～150 μm, for anti-phase polystyrene type resin, it is purchased from Mitsubishi chemical company；
Sephadex LH-20 polydextran gel, is purchased from Amersham company of Sweden；
GF254Thin layer prepared by silica gel, is purchased from Yantai Jiang You silica gel development corporation, Ltd.；
Chromatograph methanol, 4L/ bottle, it is purchased from Fisher company of the U.S.；
The analytical reagent such as petroleum ether, ethyl acetate, n-butyl alcohol, acetone, methanol, are purchased from Chengdu Ke Long chemical reagent factory.
3. experimental apparatus
Cometro 6000 high performance liquid chromatograph (U.S. Cometro)；
Waters Synapt G2HDMS high-resolution flight time mass spectrum (U.S. Waters)；
Bruker-AVIII-600 nuclear magnetic resonance analyser (Switzerland Bruker)；
Perkin-Elmer Spectrum One FT-IR infrared spectrometer (U.S. PerkinElmer)；
Xcalibur, Atlas, Gemini ultra diffractometer single crystal diffractometer (U.S. Agilent)
BP211D 100,000/electronic balance (Switzerland Sartorius)；
R-210 rotary evaporator (Switzerland BUCHI)；
DZG-6050 type vacuum drying oven (the gloomy letter in Shanghai).
(2) extraction of medical material: weigh Herba Leonuri medical material 20Kg, pulverizes, adds 95% ethanol (3 × 160L) and extract 72 hours,
Extract 3 times, after extracting solution merges, after decompression and solvent recovery, obtain ethanol extract 1.2Kg；
(3) composition is isolated and purified:
1., weighing Herba Leonuri medical material 20kg, pulverize, add 95%v/v ethanol 160L and extract 3 times, extracting solution recovered under reduced pressure is molten
After agent, obtain ethanol extract 1.2kg；
2., by ethanol extract (1.2kg) with water (8.0L) dispersion, successively with ethyl acetate (6 × 8.0L), n-butyl alcohol (6 ×
8.0L) extraction, combined ethyl acetate part, decompression and solvent recovery, obtain ethyl acetate extract 400g；
3., take ethyl acetate extract (400g), use silica gel column chromatography, according to table 1 successively with petroleum ether: acetone=100:
1,50:1,25:1,10:1,5:1,3:1,2:1,1:1,0:1 are that eluant carries out gradient elution, and taking eluant is petroleum ether-the third
Eluent during ketone (5:1), follows the trail of according to thin layer, merges the eluent containing similar compositions, recycling design, obtains component G；
Table 1, the gradient elution program of ethyl acetate extract
Take component G (12.5g), use anti-phase polystyrene type resin (MCI gel CHP 20P) column chromatography, according to table 2
Successively with methanol: water=50:50,75:25,85:15,95:5,100:0 is that eluant carries out gradient elution, taking eluant is first
Eluent when alcohol-water (85:15) and methanol-water (95:5), follows the trail of in conjunction with thin layer, merges the eluent containing similar compositions,
Recycling design, obtains component G7；
Table 2, the gradient elution program of component G
Take component G7 (1.2g), the method using alkaline silica gel column chromatography, according to table 3 successively with petroleum ether: acetone=15:
1,10:1,8:1,5:1 are that eluant carries out gradient elution, and taking eluant is eluent during petroleum ether-acetone (8:1), in conjunction with
Thin layer is followed the trail of, and merges the eluent containing similar compositions, recycling design, obtains component G7-4；
Table 3, the gradient elution program of component G7
Take component G7-4 (0.5g), by aluminum oxide column chromatography, with petroleum ether-ethyl acetate (20:1) eluting (300mL),
Employing thin layer is followed the trail of, and collects the eluent containing target compound；
Take the eluent containing target compound, recycling design, then (developing solvent is petroleum ether: acetone through preparing thin layer
=5:1) method obtain target components, then use reverse phase liquid preparative hplc, with 93%v/v methanol aqueous solution eluting, receive
Integrate retention time as tRThe target product of=75min, recycling design, obtain compound solid shown in formula II, it is entitled
(24S)-4,28-bean steroid diene-24-alcohol-3-ketone；
4. compound solid 10mg shown in modus ponens II, is placed in the glass sample bottle of 2ml, adds 0.4ml methanol, subsequently will
Sample bottle puts into the exsiccator equipped with variable color silica gel, placing until separating out colorless needles, obtaining the crystalline substance of compound shown in formula II
Type.
(4) Structural Identification of composition: clear crystal；Without skin dark stain, iodine displaing yellow, spray 10% ethanol solution of sulfuric acid at 105 DEG C
Lower displaing amaranth；By HRESIMS m/z 427.3593 [M+H]+With 449.3406 [M+Na]+, it may be determined that molecular formula is
C29H46O2。
(5) proton nmr spectra (1H-NMR): Bruker-AVIII 600spectrometer measures, and data are shown in Table 4.
Table 4,1H-NMR (600MHz) and13C NMR (150MHz) nuclear magnetic data (solvent: CDCl3；δ: ppm；J:Hz)
(6) carbon-13 nmr spectra (13C-NMR): Bruker-AVIII600spectrometer measures, and data are shown in Table 4.
(7) single crystal diffraction data are shown in Table 5.
Table 5, the single crystal diffraction data of the present invention
Compound1H NMR and13C NMR can be seen that compound is sterols parent nucleus, has 29 carbon atoms, 5 first
Base, wherein 2 unimodal methyl (δH1.17,0.70), 3 bimodal methyl (δH0.92,0.89,0.87).Contain a pair end simultaneously
Terminal double bond, hydrogen spectrum signal δH5.81 (J=17.4,10.8Hz), 5.19 (J=17.4,1.2Hz), 5.14 (J=10.8,
1.2Hz), carbon spectrum signal δC142.7,113.2.δ in composing in conjunction with carbon spectrum and hydrogenC199.9,171.9,124.0 quaternary carbon signal and low
Field proton signal δH(5.72 1H, s, H-4), it can be inferred that go out containing alpha, beta unsaturated ketone structure fragment.Additionally, according to δC 77.9
Quaternary carbon signal can be seen that containing tertiary alcohol structure.Shown by 2D-NMR experiment, this compound and report in document
Saringosterone (Z.Naturforsch.C.2003,58 (5-6): 333 336) has an identical planar structure, but relatively
For saringosterone, in compound, C-24 reaches 9.8ppm to high field displacement.Thus it is speculated that its C-24 configuration is contrary,
I.e. 24 is S configuration.
The experiment of X-ray single crystal diffraction is used to determine absolute configuration, as shown in Figure 1 further；The structure of this compound determines
For (24S)-4,28-bean steroid diene-24-alcohol-3-ketone.
In order to beneficial effects of the present invention is described, the present invention provides tests below example:
Test example 1
(1) experiment material:
1. medicine
Test-compound: (24S)-4,28-bean steroid diene-24-alcohol-3-ketone, it is configured to stocking of 1mg/mL with DMSO
Liquid ,-10 DEG C of preservations, become 25 μ g/mL, 50 μ g/mL and 100 μ g/mL with normal saline dilution before use.
2. reagent
Tetrazolium bromide (MTT).
Dimethyl sulfoxide (DMSO), cell grade, 100ml/ bottle, it is purchased from Sigma-Aldrich company.
4. cell
Human leukaemia cell system MV4-11 is purchased from Chinese Academy of Medical Sciences's Blood Research Institute.
5. experimental apparatus
Electronic balance (ESJ120-4 type, Longteng Electronic Weighing Instrument Co., Ltd., Shenyang)；Water-bath, cryogenic refrigerator etc..
(2) experimental technique:
Cell is cultivated: MV4-11 cell in the IMDM culture fluid containing 200ml/L hyclone, 37 DEG C, volume fraction
5%CO2, cultivate under the conditions of saturated humidity, choose exponential phase cell and test.
Body outer cell proliferation Inhibition test: trophophase MV4-11 cell about 2 × 10 of taking the logarithm respectively4/ mL, is added on 96 orifice plates
In.Setting up 3 concentration groups, respectively 25 μ g/mL, 50 μ g/mL and 100 μ g/mL, matched group adds the solvent of same concentration, point
Do not cultivate, calculate IC50Value.
3. experimental result and evaluation:
Found by research: the compounds of this invention (24S)-4,28-bean steroid diene-24-alcohol-3-ketone is to Leukemia Cell Lines
MV4-11 cell proliferation is inhibited, its IC50Value is 47.9 μ g/mL.
In sum, the compound of present invention offer or its crystal formation, Leukemia Cell Lines MV4-11 cell proliferation is had
Inhibitory action, provides a kind of new selection for screening treatment or prevention leukemia medicament clinically.
Claims (10)
1. compound shown in formula I:
Wherein, R1、R2、R3It is respectively selected from methyl, ethyl, propyl group or butyl.
Compound the most according to claim 1, it is characterised in that: described compound is as shown in formula II:
3. the preparation method of compound shown in formula II, it is characterised in that: it comprises the following steps:
A, take Herba Leonuri medical material, after adding ethanol extraction, remove solvent, obtain ethanol extract；
B, by ethanol extract with water-dispersible, successively with ethyl acetate, n-butanol extraction, combined ethyl acetate part, remove solvent,
Obtain ethyl acetate extract；
C, take ethyl acetate extract, use silica gel column chromatography, successively with petroleum ether: acetone=100:1,50:1,25:1,10:1,
5:1 is that eluant carries out gradient elution, takes petroleum ether: eluent during acetone=5:1, according to thin layer tracking, merging is containing phase
Like the eluent of component, recycling design, obtain component G；
D, take component G, use anti-phase polystyrene type resin column chromatography, successively with methanol: water=50:50,75:25,85:15,
95:5 is that eluant carries out gradient elution, collection methanol: eluent during water=85:15 and/or 95:5, follows the trail of according to thin layer,
Merge the eluent containing similar compositions, recycling design, obtain component G7；
E, take component G7, use alkaline silica gel column chromatography, successively with petroleum ether: acetone=15:1,10:1,8:1 is that eluant enters
Row gradient elution, collects petroleum ether: eluent during acetone=8:1, according to thin layer tracking, merging contains the eluting of similar compositions
Liquid, recycling design, obtain component G7-4；
F, take component G7-4, peroxidating aluminum column chromatography, with petroleum ether: ethyl acetate=20:1 is that eluant carries out eluting, according to
Thin layer is followed the trail of, and collects the eluent containing target compound；
G, take the eluent containing target compound, recycling design, through preparing thin layer, obtain target components, then use anti-phase
Liquid phantom preparing chromatogram, with 93%v/v methanol aqueous solution eluting, collects target compound, recycling design, to obtain final product.
Preparation method the most according to claim 3, it is characterised in that:
In step a, Herba Leonuri medical material is 1:8～24kg/L with the w/v of ethanol, and described ethanol is 95%v/v ethanol；
In step b, ethanol extract is 1.2:8kg/L with the w/v of water, and water, ethyl acetate, the volume ratio of n-butyl alcohol are
1:1～6:1～6；
In step c, the condition of gradient elution is as follows:
In step d, the condition of gradient elution is as follows:
In step e, the condition of gradient elution is as follows:
In step f, component G7-4 is 1:600g/mL with the w/v of eluant.
Preparation method the most according to claim 3, it is characterised in that:
In step d, polystyrene type resin is MCI GEL CHP 20P；
In step g, the developing solvent preparing thin layer is petroleum ether: acetone=5:1.
6. the crystal formation of compound shown in formula II, it is characterised in that: this crystal formation is monoclinic system, and space group is P21, cell parameter isα=90.00 °,β=97.2458 (13) °,γ=90.00 °, Z=4, unit cell volume is
7. the preparation method of claim 6 crystal formation, it is characterised in that: it comprises the following steps:
1., according to the method described in claim 3～5 any one, compound shown in formula II is obtained；
2., compound shown in modus ponens II, add methanol, be placed on equipped with in the exsiccator of desiccant, place to separating out crystal,
Obtain the crystal formation of compound shown in formula II.
Preparation method the most according to claim 7, it is characterised in that: step 2. in, compound shown in formula II and methanol
W/v is 1:0.01～0.1mg/mL.
9. crystal formation described in compound shown in claim 2 formula II or claim 6 is in preparation treatment or prevention leukemia medicament
Purposes.
10. a pharmaceutical composition, it is characterised in that: it be with compound shown in claim 2 formula II or its crystal formation, pharmaceutically
Acceptable salt is active component, adds the preparation that pharmaceutically conventional adjuvant prepares.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104086559A (en) * | 2014-07-09 | 2014-10-08 | 成都中医药大学 | Crystal form of diterpenoid compound |
| WO2015034010A1 (en) * | 2013-09-04 | 2015-03-12 | 学校法人常翔学園 | Intranuclear receptor liver x receptor agonist |
-
2015
- 2015-05-08 CN CN201510232749.3A patent/CN104829675B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015034010A1 (en) * | 2013-09-04 | 2015-03-12 | 学校法人常翔学園 | Intranuclear receptor liver x receptor agonist |
| CN104086559A (en) * | 2014-07-09 | 2014-10-08 | 成都中医药大学 | Crystal form of diterpenoid compound |
Non-Patent Citations (2)
| Title |
|---|
| "Biomimetic oxidation of unactivated carbons in steroids by a model of cytochrome P-450, oxorutheniumporphyrinate complex";Takashi Iida et al.;《Lipids》;20041231;第39卷(第9期);第873-880页 * |
| "Synthesis of (24R)- and (24S)-5,28-stigmastadien-3β-ol and determination of the stereochemistry of their 24-hydroxy analogs, the saringosterols";Cesar A. N.Catalan et al.;《Journal of Organic Chemistry》;19831231;第48卷(第26期);第5207-5214页 * |
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